mmg_233_2013_genetics_genomicswikiaorg-20200214-history
SNP in Alcohol Dehydrogenase Gene Offers Protection in Specific Populations
The aldehyde dehydrogenase gene (ALDH2) encodes a protein that is a critical enzyme in the alcohol metabolism pathway. When alcohol is consumed it is oxidized to acetaldehyde, which is then oxidized again to from acetic acid (Figure 1). The oxidation reactions are catalyzed by the product of the ALDH2 gene (1). ALDH2 is the mitochondrial form of the gene, while ALDH1 is cystolic, and both genes are expressed in the liver. A single nucleotide polymorphism at the rs671 locus of ALDH2 results in a non-functional form of the mitochondrial enzyme. The mutation causes a switch from glutamate to lysine at residue 504, rendering the protein product inactive (1). Heterozygosity or homozygosity for the mutant allele confers an inefficiency in alcohol metabolism, and temporary buildup of acetaldhyde occurs. Buildup is so severe in homozygous individuals acetaldhyde blood levels after drinking can be 6 to 19 fold greater than those that possess the common allele (1). Increase in acetaldhyde levels can cause nausea and facial flushing. These symptoms often discourage those that possess the allele from drinking. It was therefore hypothesized that the ALDH2 mutation could lower the risk for alcohol dependence and also play a role in the risk level of developing an alcohol related disease. Dawei Li, Hongyu Zhao, and Joel Gelernter carried out a meta-analysis, comparing the ALDH2 gene with alcohol dependence and alcohol induced disease in a comprehensive collection of english and chinese publications (1). Publication Selection This type of meta-analysis pulls data from multiple publications, and it is therefore necessary to refine and filter the information to ensure it is non-redundant and representative. Li, Zhao, and Gelernter started with 470 references matching their original query. After removal of those studies that either presented parts of the same study or did not fit the criteria imposed by the group, the genome wide association study was based upon 70 publications (1). The references were investigated thoroughly and many articles were disqualified for reasons such as ambiguities related to the definition of alcoholic or alcohol dependence, SNP coverage, lack of controls, family relation within subjects, and other similar factors (1). Association The group found that presence of the mutant allele varied greatly with regard to population. Asian populations tended to be higher for the mutant allele, Mexican American's had low rates, and European ancestry yielded no trace of the allele (1). The mutant allele and alcohol abuse and dependence showed strong association (P-value of 3 X 10^-56) overall, and even higher association in Asian populations (P-value 7X10^-56) (1). The association between alcoholic liver disease, cirrhosis, pancreatis, and the mutant allele was also high (P-value 2X10^-28). The group also looked at data subsets to ensure they were not biasing their associations. For example, they could remove all the cases of those who already knew that had liver disease or remove entire cohorts. The associations found by the group are not entirely surprising as those that have the mutant allele are often less likely to drink due to adverse reactions to alcohol, and so therefore are also less likely to develop an alcohol induced disease. The group also went through a number of steps to ensure their findings were accurate. They evaluated publication bias by using Egger's regression and Begg's rank correlation (1). Egger's regression and Begg's rank essentially work on the principal that if there is no bias towards small samples then the studies in a meta-anaylsis should show effects that vary greatest with the largest studies and least with the smallest studies. Another, more powerful, way that these techniques can be employed is to use standard error instead of sample size. The standard error versus effect variance is evaluated with regard to the the symmetry of a funnel plot with odds ratio on the X-axis and standard error on the Y. Symmetrical plots tend to indicate publication bias because you have the same effect variance coming from studies of different standard error. Assymetrical plots tend to indicate lack of publication bias for the reciprocal of the previous stated rationale. This is a rough summary, however, and there are many other things to consider when evaluating the plot and many factors which can alter the shape of the data. In the end the group concluded that there was no publication bias (1). The group also conducted heterogeneity analyses which analyzes the similarity between studies that are being used. Ideally all studies used in a meta-analysis would be carried out in the exact same way, but this is obviously not possible. Hetergeneity analyses allows the researcher to have confidence that the studies are alike enough to be used to answer the same question. Further quality control measures were carried out including sensitivity, retrospective, LD, and haplotype struture analyses. Findings The data provided by Dawei Li, Hongyu Zhao, and Joel Gelernter strongly supported their claim that the lysine mutation reduced risk for alcohol dependence and alcohol related disease in Asian populations. It makes sense that this would occur in Asian populations as they have the highest frequency for the allele (Figure 3). Because heterozygosity reduces enzyme activity 100 fold and homozygous individuals for the mutant have no ALDH2 activity, drinking causes major discomfort (1). The adverse effects caused by lack of enzyme activity push people away from drinking further and subsequently reduce their risks related to alcohol. References 1. Li, D., Zhao, H., & Gelernter, J. (2012). Strong protective effect of the aldehyde dehydrogenase gene (ALDH2) 504lys (*2) allele against alcoholism and alcohol-induced medical diseases in Asians. Hum Genet, 131(5), 725-737. doi: 10.1007/s00439-011-1116-4